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dc.creatorYang, Elaine
dc.creatorGranata, Daniele
dc.creatorEckenhoff, Roderic G.
dc.creatorCarnevale, Vincenzo
dc.creatorCovarrubias, Manuel
dc.identifier.citationElaine Yang, Daniele Granata, Roderic G. Eckenhoff, Vincenzo Carnevale, Manuel Covarrubias; Propofol inhibits prokaryotic voltage-gated Na+ channels by promoting activation-coupled inactivation. J Gen Physiol 3 September 2018; 150 (9): 1299–1316. doi:
dc.description.abstractPropofol is widely used in the clinic for the induction and maintenance of general anesthesia. As with most general anesthetics, however, our understanding of its mechanism of action remains incomplete. Local and general anesthetics largely inhibit voltage-gated Na+ channels (Navs) by inducing an apparent stabilization of the inactivated state, associated in some instances with pore block. To determine the biophysical and molecular basis of propofol action in Navs, we investigated NaChBac and NavMs, two prokaryotic Navs with distinct voltage dependencies and gating kinetics, by whole-cell patch clamp electrophysiology in the absence and presence of propofol at clinically relevant concentrations (2–10 µM). In both Navs, propofol induced a hyperpolarizing shift of the pre-pulse inactivation curve without any significant effects on recovery from inactivation at strongly hyperpolarized voltages, demonstrating that propofol does not stabilize the inactivated state. Moreover, there was no evidence of fast or slow pore block by propofol in a non-inactivating NaChBac mutant (T220A). Propofol also induced hyperpolarizing shifts of the conductance-voltage relationships with negligible effects on the time constants of deactivation at hyperpolarized voltages, indicating that propofol does not stabilize the open state. Instead, propofol decreases the time constants of macroscopic activation and inactivation. Adopting a kinetic scheme of Nav gating that assumes preferential closed-state recovery from inactivation, a 1.7-fold acceleration of the rate constant of activation and a 1.4-fold acceleration of the rate constant of inactivation were sufficient to reproduce experimental observations with computer simulations. In addition, molecular dynamics simulations and molecular docking suggest that propofol binding involves interactions with gating machinery in the S4–S5 linker and external pore regions. Our findings show that propofol is primarily a positive gating modulator of prokaryotic Navs, which ultimately inhibits the channels by promoting activation-coupled inactivation.
dc.format.extent18 pages
dc.relation.ispartofFaculty/ Researcher Works
dc.relation.haspartJournal of General Physiology, Vol. 150
dc.relation.isreferencedbyRockefeller University Press
dc.rightsAttribution-NonCommercial-ShareAlike CC BY-NC-SA
dc.subjectMolecular Pharmacology
dc.subjectMolecular Physiology
dc.titlePropofol inhibits prokaryotic voltage-gated Na+ channels by promoting activation-coupled inactivation
dc.type.genreJournal article
dc.contributor.groupInstitute for Computational Molecular Science (Temple University)
dc.ada.noteFor Americans with Disabilities Act (ADA) accommodation, including help with reading this content, please contact
dc.description.schoolcollegeTemple University. College of Science and Technology
dc.temple.creatorGranata, Daniele
dc.temple.creatorCarnevale, Vincenzo

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